Book of Abstracts - New Frontiers 2022

Abstracts of poster presentations

ANTIHYPERTENSIVE ACTIVITY OF 20-HETE ANTAGONIST (AAA) AND EPOXYEICOSATRIENOIC ACID ANALOGUE (EET-A) IN SPONTANEOUSLY HYPERTENSIVE RATS O. Gawrys 1,2 , I. Baranowska 2 , A. Walkowska 2 , Z. Husková 1 , J.R. Falck 3 , J.D. Imig 4 , E. Kompanowska-Jezierska 2 , L. Červenka 1,5 1 Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2 Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland; 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, USA; 4 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Wisconsin, USA; 5 Department of Pathophysiology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic Hypertension is one of the most significant risk factor for all-cause morbidity and mortality in the world according to WHO. The death toll of hypertension and associated disorders reaches approximately ten million deaths globally and is still on the rise despite decades of research. Increasing evidence suggest the important role of cytochrome P-450 dependent metabolites of arachidonic acid (AA) in the regulation of blood pressure. The epoxyeicosatrienoic acids (EETs) act as vasodilators, they exhibit anti-inflammatory properties and decrease sodium reabsorption. On the other hand 20-HETE is an AA metabolite with both pro- and anti-hypertensive activity. Thus we decided to explore the antihypertensive efficiency of EET-A, a stable analogue of 14,15-EET, and AAA, a novel antagonist of 20-HETE receptors. To test the antihypertensive potential of both substances we employed spontaneously hypertensive rats (SHR), which are currently considered to mimic human essential hypertension to the best extend and are widely used in pre-clinical research to develop new drug targets. Male SHR in the established stage of hypertension (16 week old) were treated for four weeks with either EET-A, AAA or the combination of EET-A and AAA and compared to age-matched untreated SHR. Both substances were administered in drinking water in a dose of 10 mg/kg/day (n=6-10). Systolic blood pressure (SBP) was measured by telemetry. Once a week observations in metabolic cages were performed; urine, blood and tissue samples were collected for further analysis. The combination of EET-A and AAA was also administered to young SHR (6 week old) in pre-hypertensive stage to evaluate the preventive potential of the new treatment. EET-A had no significant effect on blood pressure of SHR. The AAA showed some antihypertensive potential, but only the combined treatment with AAA + EET-A significantly lowered the blood pressure in adult SHR (SBP day - 2: 181±4 vs day 27: 162±5 mmHg, p<0.05). Additionally, combined AAA and EET A attenuated cardiac hypertrophy, increased natriuresis, reduced ANG II level in the kidney and increased the excretion of nitric oxide metabolites. Considering our beneficial results in adult rats we decided to test the potential of combined treatment in the prevention of hypertension development. The treatment with AAA and EET-A proved to be very beneficial for young SHR, which remained normotensive during the four- week observation (SBP on day 27: 134±2 vs 156±5 mmHg in control group, p<0.05). Taking into account all the beneficial impact of the combined treatment with EET-A and AAA on cardiovascular and renal function of SHR we suggest that it constitutes a promising antihypertensive strategy, but further research are necessary to elucidate the exact mechanism of its action.

Keywords: Hypertension, SHR, cytochrome P-450 dependent metabolites of arachidonic acid, AAA, EET-A

Funding: MH CZ - DRO (“Institute for Clinical and Experimental Medicine - IKEM, IN 00023001”) and National Science Centre Poland (2017/26/M/NZ5/00367)

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